Fendiline Enhances the Cytotoxic Effects of Therapeutic Agents on PDAC Cells by Inhibiting Tumor-Promoting Signaling
Marwa Alhothali1,2, Mevin Mathew3, Geeta Iyer4
1Department of Molecular Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, Tampa, FL 33612, USA. marwa2@mail.usf.edu.
Abstract:
The L-type calcium channel blocker fendiline has been shown to interfere with Ras-dependent signaling in K-Ras mutant cancer cells. Earlier studies from our lab had shown that treatment of pancreatic cancer cells with fendiline causes significant cytotoxicity and interferes with proliferation, survival, migration, invasion and anchorage independent growth. Currently there are no effective therapies to manage PDACs. As fendiline has been approved for treatment of patients with angina, we hypothesized that, if proven effective, combinatorial therapies using this agent would be easily translatable to clinic for testing in PDAC patients. Here we tested combinations of fendiline with gemcitabine, visudyne (a YAP1 inhibitor) or tivantinib (ARQ197, a c-Met inhibitor) for their effectiveness in overcoming growth and oncogenic characteristics of PDAC cells. The Hippo pathway component YAP1 has been shown to bypass K-Ras addiction, and allow tumor growth, in a Ras-null mouse model. Similarly, c-Met expression has been associated with poor prognosis and metastasis in PDAC patients. Our results presented here show that combinations of fendiline with these inhibitors show enhanced anti-tumor activity in Panc1, MiaPaCa2 and CD18/HPAF PDAC cells, as evident from the reduced viability, migration, anchorage-independent growth and self-renewal. Biochemical analysis shows that these agents interfere with various signaling cascades such as the activation of Akt and ERK, as well as the expression of c-Myc and CD44 that are altered in PDACs. These results imply that inclusion of fendiline may improve the efficacy of various chemotherapeutic agents that could potentially benefit PDAC patients.
Insights
Fendiline combined with YAP1 or c-Met inhibitors shows enhanced anti-tumor activity against pancreatic ductal adenocarcinoma (PDAC) cells. This combination therapy may offer a new treatment strategy for PDAC, improving efficacy and patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) lacks effective therapies.
- Fendiline, an L-type calcium channel blocker, inhibits Ras-dependent signaling in K-Ras mutant cancer cells.
- Previous studies demonstrated fendiline's cytotoxicity and anti-proliferative effects on pancreatic cancer cells.
Purpose of the Study:
- To evaluate the efficacy of combining fendiline with gemcitabine, a YAP1 inhibitor (visudyne), or a c-Met inhibitor (tivantinib) against PDAC cells.
- To determine if fendiline-based combination therapies can overcome PDAC growth and oncogenic characteristics.
- To explore potential clinical translation of fendiline for PDAC treatment, given its approval for angina.
Main Methods:
- Testing combinations of fendiline with gemcitabine, visudyne, or tivantinib in Panc1, MiaPaCa2, and CD18/HPAF PDAC cell lines.
- Assessing anti-tumor activity by measuring viability, migration, anchorage-independent growth, and self-renewal.
- Conducting biochemical analyses to investigate effects on signaling cascades like Akt and ERK, and expression of c-Myc and CD44.
Main Results:
- Combinations of fendiline with YAP1 or c-Met inhibitors demonstrated enhanced anti-tumor activity in PDAC cells.
- Significant reductions in viability, migration, anchorage-independent growth, and self-renewal were observed.
- Biochemical analysis revealed interference with Akt and ERK activation, and altered expression of c-Myc and CD44.
Conclusions:
- Fendiline in combination with YAP1 or c-Met inhibitors exhibits potent anti-PDAC activity.
- These combinations show promise for improving the efficacy of chemotherapeutic agents in PDAC treatment.
- Fendiline-based combinatorial therapies represent a potentially translatable strategy for PDAC patients.
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